Anesthetic compounds, intermediates, and processes therefor



Patented Nov. 2l, 1944 umwsmz 2 ,3 3,082 5 TE T' FF w ages-3,0 2ANESTHETIG COMPOUNDS, INTERMEDI-U WATES, AND PROCESSES THEREFOR YWilliam F. Ringk,.Hollis, Y., fassignoi'to Novo j Drawing.

This invention relates to anesthetic; in-

pounds, intermediates and processes therefor.

The principal objectof the present invention is to produce a series ofnew compounds and intermediates; as well as to produce a simplepractical process for the manufacture of the same.

Although both theintermediatesand compounds are primarily intended forproduction?! of local anesthetics, theirpse is notrestricted thereto.

The invention comprises the novel products, the specific embodiments ofwhich are described col Chemical Mfg. c corporation of New YorkApplication January20, i943, Serial No. 472,963 Y hereinafter by way ofexample and in accordance with which I now prefer toypractice theinvention.

This is a continuation-in-part of application Serial No. $06,132, filedAugustQ, 1951..

I have foundinac'cordance with myinvent'ion 7 a seriesof' substanceshaving'theformulae:

( NHaGaHq. G O O though not restricted to such use. and are made.

from the reaction of ethanols with nitro benzoyl halides asset rorthnerenartenfi Compounds ia11ing-undergroup 1 above are claimed in. mycopendingxapplication Serial No. 406,182,.fi1ed August 9, 194 1,.Compounds falling under group 2 are claimed in my copending applicationSerial No. 496589. filed July 29, 1943.

i To 1'78 -grams.(2 beta-dimethyl: ethanol and 436 grams (4 mols) ofethyl bromide contained'in afiask wasadded 900 cc, of water.

. halides asdescribed below.

o.,'Inc., Brooklyn, N. Y., a

The intermediates usedin preparing the above substances arepreparedinaccordance with my invention through the reaction, between a series ofl alkyl 1 halides and ethanol s described @below.

These, in turn are reacted jwithfgnitro. benzoyl In preparingtheselethanols, ltheljreaction mixtures are refluxed fromf24 to 96hours, depending j uponthe molecular weight ofthe alkyl group enteringthe molecule. Itis important to use an l excess of the alkyl halide;generally two mols of.

halide to one of the ethanol, in order to force the reaction to form thedesired compound). Theiolslowing is an outline of the procedure usedinpre 1. Preparation of beta-ethylumino beta, betd diparing some membersof this series.

methyl ethanol eopard-Naomi mols) of beta-amino beta,

The reaction mixture was allowed. to reflux for 24"hours, :cooled andtrans- Compounds fallingunderi group-3 are claimed herein.

- These anesthetics, especially the higher members of the series", thatiscontaining a relatively large number of carbon atomsin the alkylgroup, are particularly valuable as; surface anesthetics and findspecial use accordingly in operations 1 such as thoseon the eye.Compared with ,butyn. which is oftenemployed for eye operations, theseanesthetics of myfinvention' include compounds which, even in smallerdoses thanthose admin.- istered in the. case of butyn, give an equal orusually greater anesthetic effect.

The lower members of t his series of anesthetics are also suitable foruse in infiltration and conduction anesthesia. They have been found tobe considerably more pot'ent than procaine forfthis purpose.

ferred to a separatory funnel. The bottomlayer consisting. of unreactedethyl bromide was separated and saved; an excess-"over theamountrequired to neutralize: theHBr, .of sodium hydro-xide wasbadded. Withcooling to the fraction remaining in the separatory funnel. A whitesolid 1 mass separated from the causticsolution which was then extractedwith ether, the etherlayer separated, dried over anhydrous sodium :sulfate and the ether: evaporated off. The residue was vacuum distilled andthe fraction boiling at 84-93" C. at 21-24mm. pressurewas saved.

On careful fractionation, this yields a pure sec- ,ondary amino alcoholwhich has a B, P. (boiling peinoaie'zj-ise" I c. at atmosphericpressure. It

is a white solidhaving an MQP. (melting point) at 54.5-57.0 C, and whensu-blimed gives white, hygroscopic needles withya slight ammoniacal 2.Preparation of normal propyl amino beta dzl I -methyl ethanol To 178grams (2 mols) of beta amino beta beta dimethylethanol and492 grams (4mols) of normal propyl bromide-contained ina flask was added 900 gramsof isopropanol. The reaction mixture wasnallowed to reflux ifor:24 hoursand cooled; tAn excess of concentrated hydrochloric acid was added tothereaction mixture and the .rnixture vacuum-distilled to remove all thewater and 'isopropanoll To the residue remaining in the flask,an excessover the amount required to.

neutralizetheadded acid. of a 30% caustic alkali solution is added. Awhite solid masswas e m .tached to the nitrogen atomis ethyl, as inExwas carefully fractionated and wielded :a mum secondary amino alcoholboiling at 18l186 C. and melting at 47-49 C. It'is a-whitegsolid-andwhen sublimed gives White hygroscopicneedles with aslight ammoniacal odor. The compound has the following formula:

HO.CH2.C-NHCaH7(n.)

Z" Hz ;,,I t wl11;be;note d, in accordance with ,the above examples-.that where .the rbetaalkyl roup atample 1, that waterispreierhblynsedasa501- vent. Where ,the compound ,contains ,a. prop$0up-instead ,of th ethyhsroup iniiExample"2,,isopropanolor,similarinert.solyentis employed.

-Instead of,,.isopropano1, j;I may employ normal;

propanol or..methanol. For the .--higher members ,.,ofthe,series,.,that, is, where, such .alkylgroupcontains or ;more carbon.atoms, ea, starting with the amylcompounds, ,I tprefer to ..carry outthereaction withonteany ."solvent. For instance, in

the preparation of the octyl compound,'1 use the "followingproce'dure:

3. Preparation of beta (alpha-methyl heptyl) amino beta, beta. dimeth'ylethanol To 54 grams (0.6 mol) of beta amino beta beta dimethyl ethanolis added 117 grams (0.65 .mol) of '2-bromoctane and thiszrmixturerefluxed 'for I 'six hours and then :allowed :toxcool. :ex-

6. Beta (sec. batyl) amino beta, beta-dimethyl ethanol 10. Betaevwrmalhexylzaminodaetaslzetaedimethyl :ce'ss of a 30'% -caustic alkalisolution'uis added'rto 11. Beta (ethyl butyl) amino beta, beta-dimethylthe reaction mixture in the flask "which :causes the separation 'of a'ye11ow liquid. "This is extractedwith ether. The-etherl-ayer isseparated and dried over a suitable dryin agentwsuohas anhydrous sodiumsulfate. The ether iseva-p- 5 ',,on Q

This ..is aliquidr compound .haYings-the following ;constants:

B. P. at atmospheric pressure-=22D-226 0. D 's-10885.8.

HEC-

12. Beta-normal'heptylsamino beta beta preparation, -.the other.memhersqof this .series were-preparedas ollows 4. Beta-'isopropyl aminobeta, beta dimethyl 1.4442 1.4..-1Beta.-,normal1dec1flzammolbeta;beta-,dimethyl 5. Beta-normal @butylramz'no beta, be tmdz m weihfmfl'lethanol x am noomforrraommmna I -Ho.oH,.o-NHo-im(n) .r im

0113 :This .:-.is :;a':so1id :material :having an 3 P-.=

50-5390. B. P. at 760 mm.=295-300 C.

The above alkyl amino ethanols aremembers of the .beta alkyl amino betabeta. 'dimethyl ethanol series. In a similar manner to that employed forthe preparation of this series, the beta alkyl amino beta methyl ethanolseries may be prepared, using the known beta amino. beta methyl ethanolas one of the starting materials and reacting this with thecorresponding alkyl halide, which is also known. Using this method thefollowing secondary amino alcoh pared, having thefollovs ringconstants:l

15. a tam: amg ll amino-beta-nethyl,

ethanol B. P.=2062l4 C. at atmospheric pressure. D s =0.8812.

Similarly, using beta amino alpha. beta .dimeth- .yl ethanol, which isknown, and reacting it with ls w rl p an alkyl halide, correspondingbeta alkyl amino alpha beta dimethyl ethanols have been prepared asfollows:

17. Beta-normal b'utyl amino alpha, beta,

18. Beta-isobatyl aminoalpha, beta-dimethyl ethanol 19.Beta-normalamylamino alpha, beta I E dimethyl ethanol l 21. Beta ethylamino alphabeta dimethal ethanol .22. Beta normal propyl amino alphabeta di- 24. Beta (alpha-methyl heptyl) a ino alpha beta dimethylethanol 110.011. OH.NHGH.CaH1a on. on. CH3 B. 1 .=247-251 0. D =O.8635.11, =1.4469.

ar-0. "T

25.1Beta n rmaz deyl amino alpha eta dinzethyl 1 ethanol f 110.1011.CRNHCMHM J These amino alcohols are all colorlessliquids with aslightammoniacal odor and give a positivenitroso test for secondary aminonitrogen.

The above-mentioned ethanols are condensed with the nitro benzoyl halidein order to produce the corresponding nitro 'benzoates. which onreduction with tin or iron and hydrochloric acid constitute usefulanesthetic bases. a s ,26. Preparation of beta ethyl amino beta, beta..dimethylethyl paranitro'benzoate To grams of betaethyl amino beta betadimethyl ethanol, 8 grams of sodium hydroxide and 400 cc. of water wasadded all at onetime with vigorous stirring, 32 grams of finelypulverized para nitro benzoyl. chloride. .of the reaction mixture ismaintained between -40" C. and stirring continued until the nitro estersolidifies. The nitro ester is filtered ofi and Washed with water untilfree from alkali.

The nitro ester formed above may be reduced by conventional methods,using for instance, tin

, and hydrochloric acid, but is preferably reduced as follows? grams ofbeta ethyl amino beta, beta-di methyl ethyl para nitro benzoate,70 ramsof iron filings, 9.5 cc. of concentrated hydrochloric.

acid and 600 cc. of water are. placed in a beaker.

and stirred vigorously. The initial heat of reaction is not permittedto. go above 50 C. When thetemperature of thereaction mixture.

. starts to fall, heat is applied in order to main tain the temperaturebetween -50 C. for the entire course of. the reduction. Reduction is lThe temperature sgenerallymcomplete at the end 'of three to four hoursof vigorous stirring at'which time the reaction mixture is filtered .toremove the iron sludge. About '75 cc. of concentrated ammonium hydroxide"solution was added to thefiltrate to precipitate the amino ester whichwas then extracted with ether. The 'ether solution was evaporated andtothe amino ester was added In a similar manner, with'the exception that[for .thehigher mem bers of this series proportionately largerquantitiesof water are employed in the reduction, owing to the limitedsolubilities of the amino esterhydrochlorides in Water, the othermembers of the serieswere prepared.

27. Beta-normal propyl 'aminoibeta, beta dimethyl ethyl para-aminobenzoate hydrochloride M. P.=239-240 C. from methanol.

"28.Beta-fisopropyl amino beta, beta .dimethyl ethyl para-amino benzoatehydrochloride 29. :Beta-N-butyl amino beta, beta-dimethyl .ethyl NHz M."P.--=*'1 910-1 925 C. from methanol.

30. vBeta (sec. butyl) amino beta, beta-dimethyl -.ethyl para-amino.benzoate hydrochloride v LNH: M. Pn-EQQQ 2O5" C.

$31.' Beta isobiitylramino'beta,beta-dimtthyl'erthyl -para-:aminobenzoate hydrochloride I-NHa 32. Beta-N-amyl amino beta, beta-dimethylethyl para-amino benzoate hy'clroc'ahlcride CH3 C O O CHL-1-NHCH11 (11.).HCI I O '(EH: Nfiz M. P.=209.0-211.8 C. from water. 33. Beta -isoamyllamina -.-beta, :beta-sdimethyl ethyl para-amino benzoate hydrochlorideC O O OHab-NHCsHnfiso) .HCI

M; P;=202-203 C.1 fromrwater.

34. Beta-N-hexyl amino beta, .Ibeta-dime'thyl ethyl para-amino'benzoate'hydrochloride NHz M. P.=2l2.5-213.5 C. from'water.

'35. Beta .'(ethyl butyl) aminobe'ta, beta-dimethyl ethyl para aminobenzoate hydrochloride CH3 0211s I ooofc-mionmomihn H01 NH: This is asolid material .havingan M. .P.=.198- 199.5" C. p 36. Beta-N-heptylamino .beta, beta-tdimethyl ethyl para-amino benzoate hydrochloride OHa00.oo112.c -NHQ1Hw(n.).Hoi

M. P.'=197.0-198.0 C. from water. 37. Beta (alpha methyfheptyl)am-mammalidimethyl ethyl para 'amino benzoate hydrochloride v (ilHa V CO 0 CH2. C-NHCH. GoHunH Cl CH3 Ha- 4 M.P.='135-1'3 7?.C.fr0m Water. Theformat e salt of lthis compound, Iwhite crystals from dioxane, melts at107108;5 C. i 43 l i 38. Betd-(beta-ethyl" hemyl) amino-beta, beta-COOCHiL-NHCHLCELOAHgHGI l 39. Beta normal decyl anii-no betbeta-dimeihyl ethyl par a mlno be eoate, hydrochloride 30ml 1 i NHRP; I

This is a solid 142 0.

40. Beta normal butyl amino bath; beta-dimethyl 1 ethyl or tho a mznobenzo le material heving an M. 12:141-

o ooomnnoimo d NHz CH3 NHa M. P.=205207 C. Recrystallied from water.

42; Hydrochloride of Jbet a normal ainyl amino beta-methyl ethylpara-amino benzoate H e 00.0112. (5x11051111 (11.) .H 01

M. P.=18l3.5-18'7.5? c. Recrystallized from Weber.

43. Hydrochloride of held isoamyl amino betamethyl ethylpam aminobenzoate alpha; beta-dimethyl ethyl para amino benzoate 1.

H] H i e coon: dNuo mtmmr H3 OH: 5

iall i-le c. Recrysfie lllzed" rrbni' wai'ei; The formate salt of thiscompound, white crystals from dioxane, melts alle e-140.4? c.

45. Hydroiodide of bela-normalf amyl amino alpha, beta-dimethyl ethylpara-amino benzoate i 46. Hydfoz'odz'de of b eta-zsodmyl amino alpha,

. 2M. P.= 1 95 196.5 C. Recrystallized from water.

M.'P.=2052 O 9 C. Recrystallized from iiir zilieiu, white crystals Theformate salt of this compound from dioxane, melts at 134136 C.

l 47 LBemethyl amino alphagbeta-dimethylethyl para. amino benzoalehydrochloride Hydrochloride salt is a viscous oil.

48. Beta-normdl pfopyl amiho alphd, beta dzmethyl ethyl para-aminobenzoa te hydro z'odz'de COOCHCHNHCaHKILLHI Ha CH3 NHi 49. Beta-N-hexylamino alpha beta-dimethyl ethyl para-amino benzoate formate 44LHydroiodide I of ibetae'normal" butyl amino -50,..;Beta talphaamethyl:heptyl) sammo izalpha cbetagdimethyllethylsP-amino*benzaatenhudtochloride COOOHCHNHOHQeHmHCl CH: CH;

NHz Hydrochloride is a viscous pale yellow liquid,

. 51, Beta normaldecyl amino. alpha .b'etadimethyl ethyl para amino'benzoaie' hydrochloride C O OH C-HNH- CwHz1(n-)H Ha Ha NHz .foralonsenperiod than anyv neyeranesthetic f which Lamaw r The appendedclaims are intended to define not only an amino base or bases, but alsoa salt thereof, such as the ;;hydroch1oride, sulfate, formate, or thelike. I

The expression falkyl amino as used in the claims is intended todesignate not only the normal amino compounds but also .any isomers ofthe alkyl group. The expressions octyl amino anddecyl.aminoisimilarlyndefme both norm l mpo nd an isomersthereof.

While 'I havefdescribe'd myflimpmvQme ltsin great detail and withrespect to preferred forms thereofnl do. not, tdesireto; b l mit dtonsuchw tails ndl-ionmssince manychanees and;.-m0 cations may be madeand the invention embodied in widely differentiformsiwithout 'departingfrom the spirit and scope thereof ,in its'broader aspects. Hence, Idesire to cover all modifications, forms and embodiments coming withinthe language or scope of any one or more of the appended claims.

What I claim as new and desire to secure by Letters Patent is:

ape-swag 51. The newt-compoundghetawlkylamino;beta

substituted aethyl 23411111'10 irbenzoate {haying ithe I formula H iiNJ-Hx-CJ I-QQ Q-A a refill? I I where R is a lower alkyhgrounand the NHalk l groupecentainsino;moreithan 10 carbon atoms. I

2. The new compound, beta-alkyl amino alpha, beta-dimethyl ethyl aminobenzoate having the formula:

. H 1 NHl.-0a-Hl;oo0:o ."CLNH Alkyl V I I L0H, in which the alkylgroupcontains nomore than 10 carbon atoms. l 3. The new-compoundbeta=ethyla ialpha. beta-dimethyh ethyl para amino benzoate having the formula:

H H COOA V LNHCaHi '4. The new compound beta-octyl amino alpha,beta-dimethyl ethyl parazamino benzoate having the formula:

H .11 000.41 oNHmH" NH: ifilifl'lye new:compaun ebetaadec kammozalpha,

'beta-dimethyl ethyl para amino benzoate having the formula: I

L2H :H

a C O 0 0-.NHC10H21 N'Hz \WILIGIAMTFARINGK.

